The proposal objective is the design of newer classes and combinations of antileprosy drugs which act more rapidly than the clinically used sulfones or phenazines so that a mycobactericidal effect results in the sterilization of tissues infected with Mycobacterium leprae. It is proposed to derive structure-activity data from specific enzyme target sites compared with growth inhibition studies of antifolates and antipolymerases against cultivable mycobacterial species that are used as models for the noncultivable leprosy bacillus. A rational basis thus becomes available for selecting candidate drugs to test against M. leprae in the mouse foot pad.